Ridaforolimus

The common dysregulation of the mTOR signaling pathway in tumor cells makes it a key target in oncotherapy. To better understand the effects of mTOR inhibitors, we analyzed 32 published clinical trials on solid tumors other than renal cell cancer, neuroendocrine tumors and metastatic breast cancer, for mTOR inhibitors are already approved by the US FDA to treat the three cancers. A lack of therapeutic effects was observed when mTOR inhibitors were used as a single agent. When combined with other agents, mTOR inhibitors still lacked sufficient clinical activity or just had minimal activity. More studies are required to better understand the clinically effects of mTOR inhibitors and the development of novel mTOR inhibitors is absolutely necessary.

OBJECTIVE: Uterine serous carcinomas (USC) harbor simultaneous HER2 (ERBB2) over-expression and gain of function mutations in PIK3CA. These concurrent alterations may uncouple single agent anti-HER2 therapeutic efficacy making inhibition of the mammalian target of rapamycin (mTOR) a promising option to heighten anti-tumor response.

Combination drug therapy is a widely used paradigm for managing numerous human malignancies. In cancer treatment, additive and/or synergistic drug combinations can convert weakly efficacious monotherapies into regimens that produce robust anti-tumor activity. This can be explained in part through pathway interdependencies that are critical for cancer cell proliferation and survival. However, identification of the various interdependencies is difficult due to the complex molecular circuitry that underlies tumor development and progression. Here, we present a high-throughput platform that allows for an unbiased identification of synergistic and efficacious drug combinations. In a screen of 22,737 experiments of 583 doublet combinations in 39 diverse cancer cell lines using a 4 by 4 dosing regimen, both well-known and novel synergistic and efficacious combinations were identified. Here, we present an example of one such novel combination, a Wee1 inhibitor (AZD1775) and an mTOR inhibitor (ridaforolimus), and demonstrate that the combination potently and synergistically inhibits cancer cell growth in vitro and in vivo.

PURPOSE: The PI3K/Akt/mTOR signaling pathway is aberrantly activated in many cancers. Combining ridaforolimus, an mTOR inhibitor, with MK-2206, an Akt inhibitor, may more completely block the PI3K pathway and inhibit tumor growth.